卡维地洛与普萘洛尔降低肝硬化门静脉高压患者肝静脉压力梯度效果的对比分析

目的探讨卡维地洛和普萘洛尔降低肝硬化门静脉高压患者肝静脉压力梯度(HVPG)的幅度、应答率以及用药后不良反应的差异,对卡维地洛降低门静脉压力的有效性和安全性进行评价。方法收集2010年10月-2012年1月在山东大学附属省立医院确诊的64名肝硬化门静脉高压患者,随机分为2组:普萘洛尔组(n=33)和卡维地洛组(n=31),根据血压和心率调整剂量,疗程7 d,均于治疗前后行HVPG测定及肝肾功能指标检测,比较2组患者HVPG降低的幅度及应答率,并观察患者低血压、腹水、肾损伤等不良反应的发生情况。计量资料组间比较采用t检验,计数资料组间比较采用χ2检验或Fisher精确概率法。结果卡维地洛组和普萘洛尔组的HVPG均明显降低,降低幅度分别为(28.30±22.19)%和(12.38±24.09)%,其中卡维地洛组降低更明显,差异有统计学意义(t=0.223 4,P=0.032)。2组应答率分别为:卡维地洛组56.7%(17/30),普萘洛尔组41.9%(13/31),2组差异无统计学意义(χ2=1.324,P=0.250)。卡维地洛组平均动脉压的降低较普萘洛尔组明显,差异有统计学意义(t=2.338,P=0.024),但患者未出现明显低血压的不良反应;2组患者胆红素、血肌酐和尿素氮在治疗前后无明显升高,亦无腹水生成或加重的趋势。结论本研究提示在短期内卡维地洛降低HVPG的作用较普萘洛尔显著,且无明显不良反应;其用于肝硬化门静脉高压的治疗是安全有效的。     

Aortic hyporeactivity to norepinephrine induced by lipopolysaccharide in cirrhotic rats: beneficial effects of a non-steroidal anti-inflammatory drug coupled with a nitric oxide donor

BACKGROUND AND AIMS: Cirrhosis is associated with a hyperdynamic syndrome and arterial vasodilation that is related to nitric oxide (NO) synthase 3 overactivity. Septic shock is frequently associated with cirrhosis and with a vascular induction of NO synthase 2. The aims of this study were to compare the effects of lipopolysaccharide (LPS) in normal and cirrhotic rats, and to test the effects of a nonsteroidal anti-inflammatory drug (NSAID) coupled with a (NO) donor. METHODS: Cirrhotic rats received NO-flurbiprofen, flurbiprofen or vehicle followed by LPS or placebo 15 min later. The heart rate and mean arterial pressure of rats were monitered for 5 h. Thoracic aortic rings were removed and contracted with the use of norepinephrine. Nitric oxide synthase activity was measured in the aorta and stomach of cirrhotic rats. RESULTS: Arterial pressure decreased in cirrhotic rats in the vehicle/LPS and flurbiprofen/LPS groups. After LPS administration, the heart rate of rats increased in all groups. In the aortic rings, LPS induced hyporeactivity to norepinephrine in all groups except the NO-flurbiprofen group. This hyporeactivity was abolished after preincubation with Nw-nitro-L-arginine (L-NNA). Nw-nitro-L-arginine had no effect on norepinephrine-induced vasoconstriction in the NO-flurbiprofen/LPS group. Nitric oxide synthase 2 activity in the stomach and aorta of cirrhotic rats was increased in each group except in the NO-flurbiprofen group after LPS administration. Pretreatment with NO NSAID prevented aortic hyporeactivity to norepinephrine in cirrhotic rats treated with LPS as it probably inhibited the NO synthase 2 induction. CONCLUSIONS: These findings suggest that NO-flurbiprofen has a beneficial hemodynamic effect in cirrhotic rats and may help to prevent LPS aortic hyporeactivity.     

卡维地洛治疗肝硬化门静脉高压的研究进展

降低门体压力梯度是预防肝硬化静脉曲张出血的首要目的。卡维地洛具有非选择性阻断β受体、阻断α1受体及阻断钙通道的作用。回顾了卡维地洛在降低门静脉压力梯度方面以及预防静脉曲张出血的作用。分析表明卡维地洛较普萘洛尔可以更有效地降低门体压力梯度。卡维地洛与普萘洛尔或内镜套扎预防静脉曲张首次及再次出血疗效是相似的。未来大样本随机对照试验应该证实这些研究结果。     

Acute and 7-day portal pressure response to carvedilol and propranolol in cirrhotics

BACKGROUND: Carvedilol, a non-selective beta- and alpha-1 blocking agent, has portal hypotensive action. This study evaluates the acute and 7-day response to carvedilol, and compares it to that of propranolol. METHODS: Thirty-six cirrhotics were randomized into two groups of 18 each, and treated with carvedilol or propranolol. Hepatic venous pressure gradient (HVPG) was measured before and 90 min after either 25 mg carvedilol or 80 mg propranolol was administered orally, and again 7 days after 12.5 mg carvedilol daily or 80 mg propranolol daily, respectively. 'Responders' were defined as those with HVPG reduction of > or = 20%. RESULTS: With carvedilol, 11/18(61.1%) and 11/17(64.7%) patients responded acutely and after 7 days, respectively, while 9/18(50%) and 10/16(62.5%) did so to propranolol. However, HVPG reduction (percent) by carvedilol was not superior to that by propranolol either acutely (27.67 +/- 31.49 compared to 22.98 +/- 27.40, P = 0.6) or after 7 days (28.2 +/- 29.05 compared to 23.25 +/- 20.15, P = 0.6). With carvedilol, the acute HVPG response (P < 0.001) and responder status (P = 0.018) were good predictors of the response after 7 days, but were weak predictors in the case of propranolol (0.1 > P > 0.05 and P = 0.059, respectively). On carvedilol, only one patient (with ascites) developed symptomatic systemic hypotension with oliguria. CONCLUSION: Carvedilol is a relatively safe, effective portal hypotensive agent, both acutely and over 7 days, but not superior to propranolol, at least in Indians. The acute hemodynamic response seems promising in predicting long-term response.     

Discrepant effects of inducible nitric oxide synthase modulation on systemic and splanchnic endothelial nitric oxide synthase activity and expression in cirrhotic rats

BACKGROUND: Arterial vasodilatation, which is a major factor in the pathogenesis of the hyperkinetic circulatory state and portal hypertension in cirrhosis, is due to arterial nitric oxide (NO) overproduction secondary to endothelial NO synthase (eNOS) and inducible NOS (iNOS) upregulation. However, in cirrhosis, the respective roles of eNOS and iNOS isoforms in NO overproduction are still unknown and the effect of iNOS modulation on eNOS activity and expression has not been evaluated in the systemic or splanchnic vessels. The aim of this study was to evaluate the effects of modulating aortic and superior mesenteric arteries (SMA) iNOS on arterial eNOS activity and expression in rats with cirrhosis. METHODS: eNOS and iNOS protein expression and eNOS activity (assessed by its phosphorylation at serine 1177) were measured in the aortas and SMA in untreated and treated cirrhotic rats with lipopolysaccharide (LPS), N-iminoethyl-L-lysine (L-NIL), a selective iNOS inhibitor, and LPS plus L-NIL. RESULTS: LPS administration significantly increased eNOS and iNOS protein expression and eNOS activity in the aortas of both sham-operated and cirrhotic rats. However, in SMA, LPS administration induced a decrease in eNOS protein expression and activity and an increase in iNOS protein expression. CONCLUSION: The results of this study may explain the worsening of the hyperdynamic state in cirrhosis during septic shock by direct LPS-induced eNOS activation in large systemic vessels, and its inhibition in concomitant small splanchnic vasculature by iNOS synthesized NO.     

肝硬化门静脉高压症的诊断

门静脉高压症是消化系统常见病,指门静脉血流压力增高。肝硬化引起的门静脉高压症患病率高,目前认为由门静脉阻力(R)增加和门静脉血流量(Q)增加所致,肝脏结构改变所致的机械梗阻与神经、体液及代谢因素一同发挥着重要作用。临床表现包括腹腔积液、脾大、侧支循环形成与开放。诊断时须符合以下条件:满足肝硬化及门静脉高压症的诊断,但除外其他病因。     

Effect of early bosentan administration on the development of esophageal varices in cirrhotic rats: experimental study in Wistar rats

Background  This study was conducted to investigate the effect of chronic bosentan administration on the development of esophageal varices in carbon tetrachloride-induced cirrhosis in rats. Methods  For the development of liver cirrhosis and esophageal varices, 60 rats underwent ligation of the left adrenal vein, followed by phenobarbital and carbon tetrachloride administration. Two weeks after the beginning of carbon tetrachloride administration, rats were separated into two groups. In group I, comprising 30 rats, bosentan was continuously administered throughout the study, whereas in group II, also 30 rats, placebo instead of bosentan was continuously administered. Hemodynamic studies and morphometric analysis of the lower esophagus were performed after complete induction of cirrhosis. The total number of veins counted in the submucosa, the number of submucosal veins/mm² of submucosa, the total submucosal area occupied by vessels, the mean cross-sectional vessel area, the relative submucosal area (percentage) occupied by vessels, and the area of the single most-dilated submucosal vein were studied. Results  Bosentan induced a significant (P < 0.05) decrease in portal pressure, while morphometric analysis revealed a significant reduction (P < 0.05) of all parameters studied in bosentan-treated rats, except in the total and relative number of submucosal veins. Conclusions  Bosentan administration seemed to significantly attenuate dilation of submucosal veins in the lower esophagus of cirrhotic rats. This effect was mainly attributed to a decrease in the portal pressure induced by chronic bosentan administration.     

Endothelial,but not the inducible,nitric oxide synthase is detectable in normal and portal hypertensive rats

Abstract: Background: Chronic portal hypertension is accompanied by a nitric oxide (NO) dependent vasodilation. Three isoforms of NO producing synthases (NOS) are characterized: neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). Sources of increased NO levels in chronic hypertension is disputed. Methods: To determine eNOS and iNOS expression in different organs of portal hypertensive and control rats, we divided Sprague-Dawley rats in 6 groups: (1) Partial portal vein ligated rats, (2) Bile duct ligated rats, (3) Carbon tetrachloride treated rats, (4) Sham operated rats, (5) Untreated control rats, and (6) LPS treated rats. Immunohistochemistry (IHC) and immunoblotting (IB) using antibodies against eNOS or iNOS were carried out on samples from thymus, aorta, heart, lung, oesophagus, liver, spleen, kidney, pancreas, small and large intestine. Results: IHC revealed an even eNOS expression in all groups. Expression of iNOS was restricted to macrophages in organs of LPS treated and the thymus of rats. IB mirrored these results. Conclusion: In chronic portal hypertension, the main source for NO production depends on eNOS activity.     

一氧化氮对肝硬化大鼠肺动脉环收缩反应的影响

目的:探讨一氧化氮(NO)在肝硬化大鼠离体肺动脉对缩血管物质反应性改变中的作用.方法:采用胆总管结扎大鼠模型(组织学证实肝硬化存在,模型成功),检测给予NO合酶(NOS)抑制剂(L-NAME)前后离休肺动脉环对不同浓度苯肾上腺素(PE)的反应性.结果:肝硬化模型组大鼠离体肺动脉环对PE的收缩反应较对照组明显降低,最大收缩反应(R_(max))分别为131.51±6.95%,161.86%±11.30%,两组差异有显著意义(P<0.05).给予L-NAME预处理后,肝硬化模型组R_(max)上升至175.96±12.33%,与L-NAME处理前比较差异有显著意义(P<0.05);对照组上升至190.42±13.91%,差异无显著性(P>0.05).结论:肝硬化大鼠离体肺动脉对苯肾上腺素的反应性降低可能与NO合成增多有关     

Hemodynamic characterization in experimental liver cirrhosis induced by thioacetamide administration

Systemic and splanchnic hemodynamics in experimental liver cirrhosis in rats induced by thioacetamide were evaluated by the radioactive microsphere method. Cardiac output and regional blood flow were measured in conscious and anesthetized control and cirrhotic rats. The conscious thioacetamide-treatment rats had hyperdynamic circulation with an increased cardiac index (300±10 vs 258±3 ml/min/kg body weight,P<0.001) and increased portal venous inflow compared with the controls (64.60±2.4 vs 48.39±0.88 ml/min/kg body weight,P<0.001). Under pentobarbital anesthesia, the hyperdynamic circulation of the cirrhotic rats was maintained, with an increased cardiac index (276±7 vs 229±5 ml/min/kg body weight,P<0.001) and increased portal venous inflow compared with the controls (72.47±3.0 vs 54.08±1.2 ml/min/kg body weight,P<0.001). Portal pressure, portal venous resistance, and portal systemic shunting increased significantly while splanchnic arterial resistance decreased significantly in cirrhotic rats. Thioacetamide-induced cirrhosis is a useful model for the hemodynamic study of portal hypertension and remains useful in hemodynamic studies in the basal state under pentobarbital anesthesia.     

Pravastatin administration does not induce detrimental effects on hemodynamics and collaterals of portal hypertensive rats

Background and Aims: The 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor can enhance endothelial nitric oxide synthase expression and induce vasodilatation. The vasodilatory effect may be detrimental to portal‐systemic collaterals due to aggravating the shunting degrees. The present study investigated the effects of pravastatin, a HMG‐CoA reductase inhibitor, on the collateral vascular responsiveness to endothelin‐1 (ET‐1) and portal‐systemic shunting in portal hypertensive rats. Methods: The partial portal vein‐ligated (PVL) rats received either pravastatin (25 mg/kg per day) or distilled water since 2 days prior to until 7 days after ligation. On the 8^th day following hemodynamic measurements, the collateral vascular responsiveness to ET‐1 was evaluated by an in situ collateral perfusion model. The shunting degrees of collaterals were evaluated by constructing vascular flow‐pressure curves and color microsphere study, respectively. PVL rats underwent pre‐incubation with: (i) Krebs solution (control); or Krebs solution plus (ii) 2 × 10^?5 M pravastatin; (iii) pravastatin + N^ω‐nitro‐L‐arginine (10^?4 M); and (iv) pravastatin + indomethacin (10^?5 M), followed by ET‐1 (10^?10–10^?7 M) administration to evaluate the collateral vascular responsiveness. Results: In chronic study, pravastatin did not modify systemic and portal hemodynamics and collateral vascular responsiveness to ET‐1. The resistances of flow‐pressure curves and the microsphere study demonstrated similar shunting degrees between both groups. Furthermore, pravastatin pre‐incubation didn't reduce collateral perfusion pressure to ET‐1. Conclusion: Chronic pravastatin administration does not induce detrimental effects on hemodynamics and collaterals in PVL rats, nor does it influence the shunting degree. In addition, it does not modify the vasoconstrictive effect of ET‐1 on the collaterals of PVL rats.     

Hemodynamic effects of acute and chronic administration of vapreotide in rats with cirrhosis

The aim of this study was to assess the hemodynamic effects of acute and chronic administration of vapreotide, a somatostatin analog, in rats with intrahepatic portal hypertension induced by dimethylnitrosamine (DMNA) administration. Acute effects were evaluated at baseline and 30 min after placebo (N = 13) or vapreotide (8 g/kg/hr, N = 13) infusions in DMNA rats. Chronic hemodynamic effects were evaluated using subcutaneous implants for five weeks in anesthetized DMNA rats (placebo: N = 13, vapreotide: N = 13) and in sham rats (placebo: N = 10, vapreotide: N = 10). Hemodynamic measurements included splenorenal shunt blood flow (SRS BF) by the transit time ultrasound (TTU) method and cardiac output by the combined dilution–TTU method. Acute administration of vapreotide significantly decreased SRS BF (–17.3 ± 19 vs –1.1 ± 14%, P < 0.05) and portal pressure (–8 ± 9 vs 0 ± 8%, p < 0.05) compared to placebo without systemic effects. Chronic administration of vapreotide significantly reduced the increase in SRS BF (2.4 ± 1.5 vs 1.2 ± 1.0 ml/min, P < 0.05) and cardiac index (50 ± 15 vs 33 ± 10 ml/min/100 g, P < 0.0001) while portal pressure and blood flow, and mean arterial pressure were not significantly changed compared to placebo. In conclusion, the acute administration of vapreotide decreased collateral circulation blood flow while chronic administration attenuated its development. Vapreotide seems to have a vasoconstrictive effect on collateral circulation.     

肝硬化门脉高压症患者肝组织NO含量、NOS活性与肝功能分级的关系

目的探讨肝硬化门脉高压症患者肝组织一氧化氮（NO）和一氧化氮合酶（NOS）与肝功能分级的关系。方法用硝酸还原酶化学比色法检测56例肝硬化门脉高压症（肝硬化组;按肝功能Child分级分为A、B、C三级）及19例非肝硬化（对照组）患者的肝组织NO含量和NOS活性,分析其与肝功能分级的相关性。结果肝硬化组的肝组织NO含量、NOS活性均高于对照组,且与肝功睢分级均呈正相关（P〈0.01）.结论检测肝硬化门脉高压症患者的肝组织NO含量、NOS活性可预测其肝脏损伤程度。     

Effect of laparoscopic splenectomy on portal hypertensive gastropathy in cirrhotic patients with portal hypertension

Aim:  This study investigated the relationship between portal hypertensive gastropathy (PHG) and splenomegaly, and the effect of laparoscopic splenectomy on PHG in cirrhotic patients with portal hypertension.
Methods:  Seventy patients with liver cirrhosis and portal hypertension were prospectively studied. Indication for laparoscopic splenectomy was bleeding tendency in 10 patients, induction of interferon in 45, treatment of hepatocellular carcinoma in seven, and treatment for endoscopic injection sclerotherapy-resistant esophagogastric varices in eight. The severity of PHG was classified into none, mild, or severe according to the classification by McCormack et al. The severity of liver disease was classified using the Child–Pugh score. All patients underwent upper gastrointestinal endoscopy before and 1 month after the operation.
Results:  The prevalence of PHG was significantly correlated with the severity of liver disease using the Child–Pugh score. The severity of PHG was significantly correlated with the resected spleen volume. One month after the operation, PHG was improved in 16 of 17 patients with severe PHG and in 12 of 32 with mild PHG. The Child–Pugh score showed a significant improvement (6.8 ± 1.4 to 6.2 ± 1.2) at 3 months after laparoscopic splenectomy ( P  < 0.0001).
Conclusions:  PHG may be associated with splenomegaly, and laparoscopic splenectomy may have a beneficial effect on PHG, at least for a short time.     

A non-invasive method for evaluating cirrhotic portal hypertension by administration of 99mTc-MIBI per rectum

Abstract A study was performed to evaluate radio-isotopic imaging using technetium-99m hexakis 2-meth-oxyisobutyl isonitrile administered per rectum to assess portal collateral circulation. The heart-liver ratios (H/L; mean ± standard deviation) in 15 controls, 13 cases of histologically confirmed viral hepatitis and 57 cirrhosis patients were 0.27 ± 0.11, 0.43 ± 0.14 and 1.00 ± 0.28, respectively (P < 0.001). Among the cirrhosis patients those with the Child-Pugh classification A, B and C had H/L of 0.56 ± 0.14, 1.00 ± 0.20 and 1.19 ± 0.26, respectively (P < 0.001). A high value of H/L was associated with a high risk of hepatic encephalopathy (1.25 ± 0.17, P < 0.01) and oesophageal varices (1.02 ± 0.20, P < 0.01). There were associations between H/L and serum bilirubin (P < 0.01), albumin (P < 0.05) and prothrombin time (P < 0.05). The results also showed a good correlation between H/L and portal vein pressure measured during operation in 13 patients (P < 0.001, r= 0.87). The regression equation: y= 6.77 + 32.5 H/L, allowed portal vein pressure to be estimated. The prognostic value of the test was supported by the fact that good correlations were observed between the H/L ratio and widely accepted prognostic classification (Child-Pugh). It is suggested that this new method could be a reliable non-invasive way to give an indication of the degree of portasystemic shunting to evaluate the prognosis and to follow up the effects of medications for reducing portal hypertension in patients with cirrhotic portal hypertension.     

Liposome-mediated gene transfer of endothelial nitric oxide synthase to cirrhotic rat liver decreases intrahepatic vascular resistance

Background and Aims:  Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) in sinusoidal endothelial cells is reduced in the injured liver and leads to intrahepatic portal hypertension. The present study evaluates the effects of liposome-mediated gene transfer of eNOS on the intrahepatic vascular resistance and portal venous pressure (PVP) in cirrhotic rats.
Methods:  Hepatic cirrhosis was induced in male Sprague–Dawley rats by intraperitoneal injection of carbon tetrachloride (CCl₄), whereas the control normal rats were given the same dose of peanut oil. Plasmid eukaryotic expression vector (liposome-pcDNA3/eNOS) was injected into the portal vein of CCl₄ cirrhotic rats, whereas cirrhotic controls received the same dose of naked plasmid (liposome-pcDNA3) or Tris buffer, and control normal rats received the same dose of Tris buffer. Five days after gene transfer, the levels of eNOS mRNA and protein, NO production, PVP and the changes of hepatic intrahepatic vascular resistance were investigated.
Results:  Five days after eNOS gene transfer, the levels of eNOS mRNA, eNOS protein and NO production in cirrhotic rats increased remarkably, while hepatic vascular resistance and PVP decreased significantly in cirrhotic rats.
Conclusion:  Liposome-mediated eNOS gene transfer via intraportal injection is feasible and the increase of intrahepatic eNOS leads to a marked decrease in introhepatic vascular resistance and PVP. These data indicate that intrahepatic eNOS plays an important role in the pathogenesis of portal hypertension and gene transfer of eNOS is a potential and novel therapy for portal hypertension.